Genome-wide association studies have implicated autophagy in Crohn’s Disease (CD) pathogenesis. The functional relevance of autophagy in CD remains unknown. I hypothesized that autophagy is involved in microRNA silencing, another process implicated in CD pathogenesis. MicroRNAs are short non-coding RNAs that are loaded onto RNA-induced silencing complex (RISC) and promote degradation and/or repress translation of target mRNAs. RISC formation and turnover occurs on endosomal membranes. Since autophagosomes and endosomes are closely related and RISC components are downstream effectors of microRNA silencing, I hypothesized that autophagy affects RISC, hence modulates microRNA expression. Using immunoblotting and immunofluorescence, I showed that Ago2, a critical component of RISC, is increased in cells with defective autophagy. Using microarray technology, I discovered 5 microRNAs that are differentially expressed in these cells. Taken together, my results propose a compelling mechanism by which autophagy regulates Ago2, thereby affects miRNA expression, which is implicated in the development of CD.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/42408 |
| Date | 15 November 2013 |
| Creators | Sibony, Michal |
| Contributors | Jones, Nicola L., Silverberg, Mark |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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